ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1233T>G (p.Asp411Glu) (rs80357024)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080838 SCV000075400 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130781 SCV000185674 likely benign Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000428573 SCV000517031 likely benign not specified 2017-11-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034726 SCV000600244 likely benign not provided 2019-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000428573 SCV000698836 likely benign not specified 2020-07-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the serine-rich domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 349536 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. Though this frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00049 vs 0.001), the variant might still represent a benign polymorphism. In addition, the variant was also reported in 1/7325 European American women (frequency: 0.00014) and 2/2559 African American women (frequency: 0.0008), who were older than age 70 years and have never had cancer (in the FLOSSIES database). c.1233T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or in individuals undergoing BRCA1/2 clinical testing without strong evidence for or against pathogenicity. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000130781 SCV000903235 benign Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034726 SCV000043182 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000083166 SCV000115240 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083166 SCV000144035 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356304 SCV001551433 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and was found in 1 of 1144 chromosomes in an exome sequencing study of a control population of individuals with atherosclerosis (Johnston_2012). The variant was also identified in dbSNP (ID: rs80357024) as “With other allele”, ClinVar (as benign by SCRP, likely benign by Invitae, Ambry Genetics, and GeneDx, and uncertain significance by Quest Diagnostics, BIC and Biesecker Lab), Clinvitae (5x), LOVD 3.0 (3x), UMD-LSDB (4x), and BIC Database (4x) databases. The variant was not identified in COGR, Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276576 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 24008 chromosomes (freq: 0.000417), Latino in 1 of 34402 chromosomes (freq: 0.000029), and not in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. There are conflicting interpretations in the literature for this variant. Studies based on amino acid conservation classify the variant as neutral (Abkevich_2004, Burk-Herrick_2005), while a study of splicing effects (Mucaki_2010) and a study of early onset breast cancer patients (Maxwell_2014) both classified the variant as unknown significance. The p.Asp411 residue is not conserved in mammals and the variant amino acid Glutamine (Glu) is present in Red junglefowl, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site. However, HumanSpliceFinder, MaxEntScan, and GeneSplicer predict an altered 5' splice site in this region and Human Splicing Finder predicts an altered 3’ splice site; therefore we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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